SHP-1 activation inhibits vascular smooth muscle cell proliferation and intimal hyperplasia in a rodent model of insulin resistance and diabetes

Weier Qi,Mogher Khamaisi,Xuanchun Wang,Samuel M Lockhart,Chong Wee Liew,Lars Melholt Rasmussen,Qian Li,Kevin Croce,Christian Rask-Madsen,Yu Xia,George L King

doi:10.1007/s00125-016-4159-1

Abstract

Aims/hypothesisAccelerated migration and proliferation of vascular smooth muscle cells (VSMCs) enhances arterial restenosis after angioplasty in insulin resistance and diabetes. Elevation of Src homology 2-containing protein tyrosine phosphatase 1 (SHP-1) induces apoptosis in the microvasculature. However, the role of SHP-1 in intimal hyperplasia and restenosis has not been clarified in insulin resistance and diabetes.MethodsWe used a femoral artery wire injury mouse model, rodent models with insulin resistance and diabetes, and patients with type 2 diabetes. Further, we modulated SHP-1 expression using a transgenic mouse that overexpresses SHP-1 in VSMCs (Shp-1-Tg). SHP-1 agonists were also employed to study the molecular mechanisms underlying the regulation of SHP-1 by oxidised lipids.ResultsMice fed a high-fat diet (HFD) exhibited increased femoral artery intimal hyperplasia and decreased arterial SHP-1 expression compared with mice fed a regular diet. Arterial SHP-1 expression was also decreased in Zucker fatty rats, Zucker diabetic fatty rats and in patients with type 2 diabetes. In primary cultured VSMCs, oxidised LDL suppressed SHP-1 expression by activating Mek-1 (also known as Map2k1) and increased DNA methylation of the Shp-1 promoter. VSMCs from Shp-1-Tg mice exhibited impaired platelet-derived growth factor (PDGF)-stimulated tyrosine phosphorylation with a concomitant decrease in PDGF-stimulated VSMC proliferation and migration. Similarly, HFD-fed Shp-1-Tg mice and mice treated with the SHP-1 inducer, Icariside II, were protected from the development of intimal hyperplasia following wire injury.Conclusions/interpretationSuppression of SHP-1 by oxidised lipids may contribute to the excessive VSMC proliferation, inflammatory cytokine production and intimal hyperplasia observed in arteries from diabetes and insulin resistance. Augmenting SHP-1 levels is a potential therapeutic strategy to maintain stent patency in patients with insulin resistance and diabetes.

Highlights

A prominent feature in the pathology of restenosis and atherosclerosis is the increased number of vascular smooth muscle cells (VSMCs) in the intima of arteries due to enhanced VSMC migration and proliferation [1, 2]
Conclusions/interpretation Suppression of Src homology 2-containing protein tyrosine phosphatase 1 (SHP-1) by oxidised lipids may contribute to the excessive VSMC proliferation, inflammatory cytokine production and intimal hyperplasia observed in arteries from diabetes and insulin resistance
high-fat diet (HFD) feeding enhances femoral artery intimal hyperplasia in response to wire injury To determine whether insulin resistance and diabetes increased intimal hyperplasia, wire injury in the femoral artery was performed on mice fed either a regular diet (RD) or an HFD (60% energy from fat) for 4 weeks starting from the age of 8 weeks

Summary

Introduction

A prominent feature in the pathology of restenosis and atherosclerosis is the increased number of vascular smooth muscle cells (VSMCs) in the intima of arteries due to enhanced VSMC migration and proliferation [1, 2]. There is disagreement in the literature about whether the expression of these growth factors is increased in the vascular wall or plasma in the context of diabetes [10]. It is still unclear if this mechanism drives excessive VSMC proliferation in the diabetic milieu

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